cell differentiation

HL-60 retains the capability to undergo GO arrest and differentiation along either the myeloid or the monocytic lineages. For example, retinoic acid causes GO arrest and myeloid differentiation, whereas 1,25-dihydroxy vitamin D3, a ligand for another member of the same steriod thyroid hormone receptor superfamily, causes arrest and monocytic differentiation. This established cell line has been one of the archtypical models for studies of myelo-monopoiesis and hematopoietic differentiation. Because it is derived from a patient with acute promyelocytic leukemia, a disease where retinoic acid has now been found to induce temporary remissions while conventional chemotherapy has not been effective, there is significant motivation for understanding its mechanism of action. The current work focuses on what retinoid receptors are implicated in initiating the metabolic cascade culminating in GO arrest and cell differentiation, how that process is modulated by cell surface receptors such as c-FMS (the CSF-1 receptor) that use MAPK signaling, and how the RB (retinoblastoma tumor suppressor) protein may function as a downstream effector of these signals to regulate cell cycle and cell differentiation. One of the central scientific questions addressed in the laboratory is the cellular molecular mechanisms of myeloid and monocytic cell differentiation.

The application of basic principles elucidated in these in vitro studies is directed toward understanding the mechanism of teratogenic agents and also toward the rational design of differentiation induction therapy of cancer. Whereas conventional chemotherapy seeks to expunge the tumor stem cell population, this alternative seeks to nullify the proliferative activity and differetiatively immature hallmarks of the tumor by inducing terminal differentiation. The host can thus be relieved of the tumor burden. The hope is that this potential form of therapy will spare the host of the severely toxicity inherent in conventional chemotherapy. Significantly certain dietary factors and environmental pollutants can induce terminal differentiation of neoplastic cells. The molecular mechanism by which they act is being studied by the above.